Benveniste et al. found a factor which strongly induced platelet aggregation from rabbit basophils, and named as platelet-activating factor (hereinunder referred to as PAF) in 1972. Hanahan et al. identified that the factor was phosphoglyceride of alkyl ether type having acetyl group in the 2-position, i.e. 1-o-hexadecyl or octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, in 1980.
The physiological roles of PAF have been intensively investigated, and it has been known that PAF was an important factor of various physiological reactions inclusive of platelet aggregation, reduction in blood pressure, immediate allergic reaction, contraction of smooth muscle, inflammation, pain, edema, as well as alteration in the respiratory, cardiovascular and venous systems.
Therefore, PAF-antagonistic activity-possessing compounds are considered to be very useful for various PAF-induced diseases such as inflammatory diseases, allergic diseases, anaphylactic shocks, septic shocks, vascular diseases as DIC, myocardial diseases, asthma, pulmonary edema or adult respiratory diseases.
Japanese Journal of Pharmacology, vol. 44, pp. 381-391 (1987) discloses that antianxietic or anticonvulsant Etizolam (Recommended INN of 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4] diazepine) exhibits antagonistic activity on PAF. EP-A 194416 discloses that thienotriazolo-1,4-diazepine-2-carboxylic acid amide compounds represented by 4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]dia zepine-2-propionic acid morpholide exhibit antagonistic activity on PAF, and also EP-A 230942, EP-A 240899 and EP-A 254245 disclose 1,4-diazepine derivatives with PAF antagonistic activity, respectively.
Recently, 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepin-2-yl]propionic acid morpholide (WEB 2086) or 5-(2-chlorophenyl)-3,4-dihydro-10-methyl-3-morpholinomethyl-2H,7H-cyclopen ta[4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (STY 2108) are known to exhibit more potent PAF-antagonistic activity However, such compounds are not yet sufficient in view of the separation from the effect on the central nervous system, the potency, the effectiveness by the oral administration or the duration of activity Therefore, it is desirable to provide potent PAF-antagonistic compounds which possess not only effectiveness by oral administration and long-lasting effect, but also less inhibitory effect on the central nervous system.
The present inventors have made intensive investigations in view of the above respects and found in a series of the investigations that an introduction of substituent such as alkyl into the diazepine core of the thienotriazolodiazepine compounds has made the PAF-antagonistic activity more potent, effective by oral administration and long-lasting, and furthermore it has made easier to separate the activity from the effect on the central nervous system such as sedative activity or muscle relaxation activity because such activities remarkably decreased, and finally completed the present invention.